Lumen Of Small Intestine Research Articles

Clinical assessment of small bowel capsule endoscopy in pediatric patients.

Small bowel capsule endoscopy is a first-line examination method for small bowel diseases, which can find small intestinal lumen and mucosal lesions. We retrospectively assessed patients who underwent small bowel capsule endoscopy between September 2020 and May 2023 to examine their clinical and small bowel capsule endoscopic data, aiming to provide insights into the application of this technique in pediatric patients with small intestinal diseases. All instances of capsule retention were successfully resolved through enteroscopy. Of the 1140 children who completed the capsule endoscopy, 97.46% (1111/1140) underwent a comprehensive examination of the entire small intestine without experiencing any discomfort. Capsule endoscopy yielded abnormal findings in 672 cases, with a positive detection rate of 58.95%. Among the positive results, intestinal mucosal inflammatory lesions were the most prevalent, occurring in 292 cases (43.45%), followed by ulcerative or erosive lesions in 236 cases (35.12%), diverticulum in 54 cases (8.04%), and vascular lesions in 30 cases (4.46%). Lymphangiectasis was observed in 16 cases (2.38%). The distribution of positive lesions did not exhibit significant gender-based differences, but there were variations among different age groups. Among all children who completed the small bowel capsule endoscopy, the most frequently reported symptom was abdominal pain (815/1140 cases, 71.49%), followed by 130 cases (11.40%) of bloody stools or melena. Small bowel capsule endoscopy is well-tolerated and safe in children, carrying significant clinical importance for diagnosing abdominal pain and obscure gastrointestinal bleeding in pediatric patients.

Tunneling Nanotube-like Structures in Giardia duodenalis.

Giardia doudenalis (lamblia, intestinalis) is a protozoan parasite that inhabits the lumen of the upper small intestine of vertebrates, causing chronic abdominal pains and severe diarrhea, symptoms of giardiasis, a persistent and recurrent infection. This characteristic is mainly due to the presence of membrane variant-specific surface proteins (VSPs) that give this parasite the ability to successively infect the host through antigenic variation. Using high-resolution scanning microscopy (HR-SM), we observed the presence, formation, and extension of tunneling-nanotube-like surface structures in Giardia, especially following parasite challenges with VSP antibodies. They were seen all over the parasite surface, both in vitro and in vivo, showing that G. duodenalis nanotube formation occurs in complex environments such as the gut. In addition, we also observed that some of these nanotubes displayed a periodic strangulation that produces 100 nm vesicles that seemed to be released in a process similar to that previously observed in Trypanosoma brucei. The presence of nanotube-like structures in G. duodenalis highlights yet another strategy of cellular communication utilized by these parasites, whether between themselves or with the host cell.

Ascaris suum infection in juvenile pigs elicits a local Th2 response in a setting of ongoing Th1 expansion.

Ascaris spp. undergo extensive migration within the body before establishing patent infections in the small intestinal tract of humans and pigs. However, whether larval migration is critical for inducing efficient type 2 responses remains poorly understood. Therefore, we investigated systemic versus local adaptive immune responses along the hepato-tracheal migration of Ascaris suum during primary, single infections in conventionally raised pigs. Neither the initial invasion of gut tissue nor migration through the liver resulted in discernable Th2 cell responses. In contrast, lung-stage larvae elicited a Th2-biased pulmonary response, which declined after the larvae had left the lungs. In the small intestine, we observed an accumulation of Th2 cells upon the arrival of fourth-stage larvae (L4) to the small intestinal lumen. In parallel, we noticed robust and increasing Th1 responses in circulation, migration-affected organs, and draining lymph nodes. Phenotypic analysis of CD4+ T cells specifically recognizing A. suum antigens in the circulation and lung tissue of infected pigs confirmed that the majority of Ascaris-specific T cells produced IL-4 (Th2) and, to a much lesser extent, IL-4/IFN-g (Th2/1 hybrids) or IFN-g alone (Th1). These data demonstrate that lung-stage but not the early liver-stage larvae lead to a locally restricted Th2 response. Significant Th2 cell accumulation in the small intestine occurs only when L4 complete the body migration. In addition, Th2 immunity seems to be hampered by the concurrent, nonspecific Th1 bias in growing pigs. Together, the late onset of Th2 immunity at the site of infection and the Th1-biased systemic immunity likely enable the establishment of intestinal infections by sufficientlylarge L4 stages and pre-adult worms, some of which resist expulsion mechanisms.

Ethyl Acetate Fractions of Tectona Grandis Crude Extract Modulate Glucose Absorption and Uptake as Well as Antihyperglycemic Potential in Fructose-Streptozotocin-Induced Diabetic Rats.

Type 2 diabetes (T2D) is a global health challenge with increased morbidity and mortality rates yearly. Herbal medicine has provided an alternative approach to treating T2D with limited access to formal healthcare. Tectona grandis is being used traditionally in the treatment of diabetes. The present study investigated the antidiabetic potential of T. grandis leaves in different solvent extractions, and the crude extract that demonstrated the best activity was further fractionated through solvent-solvent partitioning. The ethyl acetate fraction of the ethanol crude extract showed the best antidiabetic activity in inhibiting α-glucosidase, delaying glucose absorption at the small intestine's lumen, and enhancing the muscle's postprandial glucose uptake. The ethyl acetate fraction was further elucidated for its ability to reduce hyperglycemia in diabetic rats. The ethyl acetate fraction significantly reduced high blood glucose levels in diabetic rats with concomitant modulation in stimulated insulin secretions through improved pancreatic β-cell function, insulin sensitivity by increasing liver glycogen content, and reduced elevated levels of liver glucose-6-phosphatase activity. These activities could be attributed to the phytochemical constituents of the plant.

Clinical Presentation of Small Intestinal Bacterial Overgrowth from Aerodigestive Tract Bacteria Versus Colonic-Type Bacteria: A Comparison Study.

Small Intestinal Bacterial Overgrowth (SIBO) is a heterogenous syndrome from excessive bacteria in the small intestine lumen. It is unknown if differences in type of bacterial overgrowth lead to differences in symptoms. Patients with suspected SIBO were recruited prospectively. Exclusion criteria were probiotics, antibiotics, or bowel prep in preceding 30days. Clinical characteristics, risk factors, and labs were collected. Proximal jejunal aspiration via upper enteroscopy was performed. Aerodigestive tract (ADT) SIBO was defined as > 105CFU/mL of oropharyngeal and respiratory bacteria. Colonic-type SIBO was defined as > 104CFU/mL of distal small bowel and colon bacteria. Aims were to compare symptom profiles, clinical complications, labs, and underlying risk factors between ADT and colonic-type SIBO. We consented 166 subjects. Aspiration was not obtained in 22 and SIBO was found in 69 (49%) of 144 subjects. Daily abdominal distention trended towards more prevalent in ADT SIBO versus colonic-type SIBO (65.2% vs 39.1%, p = 0.09). Patient symptom scores were similar. Iron deficiency was more prevalent in ADT SIBO (33.3% vs 10.3%, p = 0.04). Subjects with colonic-type SIBO were more likely to have a risk factor for colonic bacteria colonization (60.9% vs 17.4%, p = 0.0006). Subjects with ADT SIBO were more likely to have a risk factor for diminished gastric acid (91.3% vs 67.4%, p = 0.02). We found differences in iron deficiency and underlying risk factors between ADT and colonic-type SIBO. However, distinct clinical profiles remained elusive. Future research is needed to develop validated symptom assessment tools and distinguish cause from correlation.

Chronic inflammatory enteropathy: faecal microbiota transplantation in clinical practice

Chronic inflammatory enteropathy is an umbrella term that encompasses various inflammatory disorders of the gastrointestinal tract. In the absence of identifiable underlying infectious, neoplastic or metabolic causes, chronic or recurrent signs of gastrointestinal disease and histopathological evidence of mucosal inflammation are the hallmarks of chronic inflammatory enteropathy. Subgroups of chronic inflammatory enteropathy are retrospectively categorised as food-responsive, immunosuppression-responsive, small intestinal dysbiosis or non-responsive based on the selective response to therapeutic trials. Small intestinal dysbiosis is an overarching term used to describe derangement of the small intestinal microbiota caused by an abnormal proliferation of bacteria and/or change in bacterial species present in the small intestinal lumen. The pathogenesis of chronic inflammatory enteropathy remains elusive, although current hypotheses emphasise the role of adverse immune responses to dietary and microbial antigens thought to arise from immune system dysregulation, genetic susceptibility and intestinal dysbiosis. The gastrointestinal tract of dogs is colonised by a vast population of microorganisms, known as the intestinal microbiota, which is composed of viruses, fungi, bacteria and protozoa. Clinical use of faecal microbiota transplantation in promoting normobiosis has been gaining popularity within the field of canine gastroenterology. This modifies the intestinal bacterial microbiota and has shown promise as an adjunctive treatment of enteric disease, associated with a faster resolution of diarrhoea and enhanced clinical recovery.

Increased bioavailability of a P-gp substrate: Co-release of etoposide and zosuquidar from amorphous solid dispersions

P-glycoprotein (P-gp) inhibitors, like zosuquidar, partly increase oral bioavailability of P-gp substrates, such as etoposide. Here, it was hypothesised that co-release of etoposide and zosuquidar from amorphous solid dispersions (ASDs) may further increase oral etoposide bioavailability. This was envisioned through simultaneous co-release and subsequent spatiotemporal association of etoposide and zosuquidar in the small intestinal lumen. To further achieve this, ASDs of etoposide and zosuquidar in polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) 5, and HPMC 4 k were prepared by freeze-drying. From these ASDs, etoposide release was fastest from PVP, then HPMC 5 and slowest from HPMC 4. Release from PVP and HPMC5 resulted in stable supersaturations of etoposide. In transcellular permeability studies across MDCKII-MDR1 cell monolayers, the accumulated amount of etoposide increased 3.7–4.9-fold from amorphous etoposide or when incorporated into PVP- or HPMC 5-based ASDs, compared to crystalline etoposide. In vivo, the oral bioavailability in Sprague Dawley rats increased from 1.0 to 2.4–3.4 %, when etoposide was administered as amorphous drug or in ASDs. However, when etoposide and zosuquidar were co-administered, the oral bioavailability increased further to 8.2–18 %. Interestingly, a distinct increase in oral etoposide bioavailability to 26 % was observed when etoposide and zosuquidar were co-administration in HPMC5-based ASDs. The supersaturation of etoposide as well as the simultaneous co-release of etoposide and zosuquidar in the small intestinal lumen may explain the observed bioavailability increase. Overall, this study suggested that simultaneous co-release of an amorphous P-gp substrate and inhibitor may be a novel and viable formulation strategy to increase the bioavailability P-gp substrates.

Human Milk-Fed Piglets Have a Distinct Small Intestine and Circulatory Metabolome Profile Relative to That of Milk Formula-Fed Piglets

The impact of human milk (HM) feeding compared with cow's milk formula (MF) feeding on small intestinal and circulatory metabolome patterns has not been fully investigated. Therefore, 2-day-old male piglets were fed HM or MF (n = 26/group) from postnatal day 2 (PND 2) through 21 and were weaned to a solid diet until PND 51. The small intestine (gastrointestinal [GI]) contents, serum, and urine were collected from subsets of piglets at PND 21 and PND 51. Samples were subjected to primary metabolomics analyses at the West Coast Metabolomics Center, UC Davis. The metabolome data assessment and the statistical analyses were performed with MetaboAnalyst software. Compared with MF feeding, at PND 21, HM feeding resulted in a higher abundance of fucose in the jejunum and urine and a greater concentration of myo-inositol in serum. In HM-fed piglets, 1,5-anhydroglucitol was higher in the duodenum, serum, and urine at PND 21. Additionally, the HM group had higher levels of urinary kynurenic acid at PND 21. Correlations between bacterial genera and altered metabolites in ileum revealed that Turicibacter sp. and Campylobacter sp. were positively correlated with maltotriose and panose at PND 21, while ileal Campylobacter sp. was negatively correlated with fumaric acid. At PND 51, no significant metabolites were identified between HM and MF diet groups. The metabolites associated with the neonatal diets may serve as the substrates and signals that contribute to the physiological effects in HM and MF during infancy, with a subset reflecting diet-associated differences in microbial metabolism and ecology.IMPORTANCE Exclusive HM feeding for newborns is recommended at least for the first 6 months of life. However, when breastfeeding is not possible, MF is recommended as a substitute. Due to the challenges associated with sample collection from infants fed HM or MF, their gut metabolism is poorly understood. Thus, an established piglet model from our team was used to determine the metabolite profile in relation to host, diet, and microbiota. The current study is the first to provide novel insights across the small intestine metabolism and its association with circulatory metabolites in the HM group relative to the MF group at the weaning and postweaning period. Data also demonstrate that during the neonatal period, diet, host, and microbial metabolism contribute to the lumen and circulatory metabolite profile. Furthermore, small intestinal lumen metabolome can be tracked in the urine as a biomarker of dietary differences, which would be a useful tool for clinical interventions.

Impaired host resistance to Salmonella during helminth co-infection is restored by anthelmintic treatment prior to bacterial challenge.

Intestinal helminth infection can impair host resistance to co-infection with enteric bacterial pathogens. However, it is not known whether helminth drug-clearance can restore host resistance to bacterial infection. Using a mouse helminth-Salmonella co-infection system, we show that anthelmintic treatment prior to Salmonella challenge is sufficient to restore host resistance to Salmonella. The presence of the small intestine-dwelling helminth Heligmosomoides polygyrus at the point of Salmonella infection supports the initial establishment of Salmonella in the small intestinal lumen. Interestingly, if helminth drug-clearance is delayed until Salmonella has already established in the small intestinal lumen, anthelmintic treatment does not result in complete clearance of Salmonella. This suggests that while the presence of helminths supports initial Salmonella colonization, helminths are dispensable for Salmonella persistence in the host small intestine. These data contribute to the mechanistic understanding of how an ongoing or prior helminth infection can affect pathogenic bacterial colonization and persistence in the mammalian intestine.

Inverted Meckel's diverticulum associated with heterotopic pancreatic tissue causing intestinal obstruction: a case report

BackgroundMeckel’s diverticulum is the most frequent congenital anomaly of the gastrointestinal tract. It can invert or invaginate into the small intestine lumen. It is usually associated with heterotopic tissue elements.Case presentationWe present a case of inverted Meckel's diverticulum, clinically and radiologically diagnosed as intestinal obstruction due to intussusceptions. The diagnosis was suspected due to target sign shown on radiological examination. Pathologically, it was inverted Meckel's diverticulum obstructing the lumen in parallel plan mimicking the telescoping appearance, with heterotopic pancreatic tissue formed of exocrine and ductal components only.ConclusionsInverted Meckel’s diverticulum may present by vague symptoms and may simulate other causes of intestinal obstruction.

Metabolomics analysis of time-series human small intestine lumen samples collected in vivo.

The human small intestine remains an elusive organ to study due to the difficulty of retrieving samples in a non-invasive manner. Stool samples as a surrogate do not reflect events in the upper gut intestinal tract. As proof of concept, this study investigates time-series samples collected from the upper gastrointestinal tract of a single healthy subject. Samples were retrieved using a small diameter tube that collected samples in the stomach and duodenum as the tube progressed to the jejunum, and then remained positioned in the jejunum during the final 8.5 hours of the testing period. Lipidomics and metabolomics liquid chromatography tandem mass spectrometry (LC-MS/MS) assays were employed to annotate 828 unique metabolites using accurate mass with retention time and/or tandem MS library matches. Annotated metabolites were clustered based on correlation to reveal sets of biologically related metabolites. Typical clusters included bile metabolites, food metabolites, protein breakdown products, and endogenous lipids. Acylcarnitines and phospholipids were clustered with known human bile components supporting their presence in human bile, in addition to novel human bile compounds 4-hydroxyhippuric acid, N-acetylglucosaminoasparagine and 3-methoxy-4-hydroxyphenylglycol sulfate. Food metabolites were observed passing through the small intestine after meals. Acetaminophen and its human phase II metabolism products appeared for hours after the initial drug treatment, due to excretion back into the gastrointestinal tract after initial absorption. This exploratory study revealed novel trends in timing and chemical composition of the human jejunum under standard living conditions.

Thymic carcinoma metastasize to the small intestine: a case report

BackgroundThymic carcinoma is a rare mediastinal neoplasm with a high malignant potential. It often shows pleural invasion and distant metastasis. The metastasis of thymic carcinoma to the small intestine is rarely reported and difficult to distinguish from other gastrointestinal tract tumors.Case presentationAn elderly man presented with lower abdominal pain for 2 months. Abdominal CT showed a mass communicated with the small intestinal lumen. After radical resection of the small intestinal tumor, resected specimens showed moderately differentiated squamous-cell carcinoma with lymph nodes metastases. The patient received chest CT and was found to have a mass in anterior mediastinum. Biopsies of the mass revealed thymic squamous-cell carcinoma.ConclusionsWe highlighted the metastasis of thymic carcinoma to the small intestine is rare and easily misdiagnosed. In patients with a mass communicated with the small intestinal lumen, a suspicion of thymic carcinoma metastasis should not be overlooked and we should make accurate differential diagnosis from the other small intestinal tumors.

Endocannabinoids, endocannabinoid-like molecules and their precursors in human small intestinal lumen and plasma: does diet affect them?

PurposeTo determine the small intestinal concentration of endocannabinoids (ECs), N-acylethanolamines (NAEs) and their precursors N-acylphosphatidylethanolamines (NAPEs) in humans. To identify relationships between those concentrations and habitual diet composition as well as individual inflammatory status.MethodsAn observational study was performed involving 35 participants with an ileostomy (18W/17M, aged 18–70 years, BMI 17–40 kg/m2). Overnight fasting samples of ileal fluid and plasma were collected and ECs, NAEs and NAPEs concentrations were determined by LC-HRMS. Dietary data were estimated from self-reported 4-day food diaries.ResultsRegarding ECs, N-arachidonoylethanolamide (AEA) was not detected in ileal fluids while 2-arachidonoylglycerol (2-AG) was identified in samples from two participants with a maximum concentration of 129.3 µg/mL. In contrast, mean plasma concentration of AEA was 2.1 ± 0.06 ng/mL and 2-AG was 4.9 ± 1.05 ng/mL. NAEs concentrations were in the range 0.72–17.6 µg/mL in ileal fluids and 0.014–0.039 µg/mL in plasma. NAPEs concentrations were in the range 0.3–71.5 µg/mL in ileal fluids and 0.19–1.24 µg/mL in plasma being more abundant in participants with obesity than normal weight and overweight. Significant correlations between the concentrations of AEA, OEA and LEA in biological fluids with habitual energy or fat intakes were identified. Plasma PEA positively correlated with serum C-reactive protein.ConclusionWe quantified ECs, NAEs and NAPEs in the intestinal lumen. Fat and energy intake may influence plasma and intestinal concentrations of these compounds. The luminal concentrations reported would allow modulation of the homeostatic control of food intake via activation of GPR119 receptors located on the gastro-intestinal mucosa.Clinical trial registry number and websiteNCT04143139; www.clinicaltrials.gov.

S2853 Metastatic Lung Adenocarcinoma Presents as Small Bowel Perforation

INTRODUCTION: Lung adenocarcinomas are often diagnosed at the advanced stage of disease and gastrointestinal metastases from pulmonary neoplasms are rare with the incidence of 0.2-0.5%. Early diagnosis of small intestinal metastasis is difficult due to the low incidence of symptoms and scarcity of imaging modalities to evaluate small intestinal lumen. Here, we present a case of visceral perforation of the ileum from lung adenocarcinoma metastasis. CASE DESCRIPTION/METHODS: A 61 years old Caucasian male with a history of lung adenocarcinoma and metastatic lymphadenopathy presented with severe acute abdominal pain. A recent PET scan revealed interval improvement of the lung mass with decreasing nodal sizes after chemotherapy with docetaxel and ramucirumab. Vital signs were unremarkable and physical examination revealed a distended abdomen with significant abdominal tenderness, involuntary guarding, and Blumberg sign. Laboratory results noted marked leukocytosis of 30,000 per microliter with 16% band neutrophils. Computerized tomography (CT) of the abdomen and pelvis revealed extraluminal gas and ruptured viscus (Figure 1). Exploratory laparotomy revealed mid ileal perforation and a totally constricted lumen. The patient underwent resection of 30 cm of the mid-ileum with end-to-end anastomosis. Histology (Figure 2) and immunochemistry (Figure 3) findings were similar to the carcinoma in the previous nodal biopsy. The patient was referred to outpatient oncology follow-up with chemotherapy and a short-term follow up in 6 months was uneventful. DISCUSSION: Perforations occurs more commonly in Jejunum (53%) than ileum (28%). Histological type associated with gastrointestinal metastasis is still unclear. Small bowel perforation can occur even with a favorable prognosis as evidenced by our patient’s staging PET/CT scan showing improved tumor burden. Once metastasis occurred to small bowel, they trend to perforate due to tumor necrosis rather than obstruction. Intestinal tumor metastases are uncommon but should be considered in the diagnosis of a patient with an acute abdomen with a history of pulmonary neoplasm. The surgical approach is mandatory even as a palliative measure. Preoperatively establishing, or suspecting, a diagnosis of metastases to the small bowel can help inform surgical planning and ultimately enhance outcomes.Figure 1.: Coronal Imaging of computed tomography (CT) of the abdomen pelvis with contrast revealed extraluminal gas and ruptured viscus (white circle).Figure 2.: Small bowel resection showing poorly differentiated adenocarcinoma (hematoxylin-eosin, original magnification 40X).Figure 3.: Small bowel resection poorly differentiated adenocarcinoma showing positive TTF-1 nuclear expression by immunohistochemistry most consistent with metastatic poorly differentiated adenocarcinoma of lung primary (original magnification 200X).

Acupuncture improved lipid metabolism by regulating intestinal absorption in mice.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD), in which abnormal lipid metabolism plays an important role in disease progression, has become a pandemic. Abnormal lipid metabolism, for example an increased fat intake, has been thought to be an initial factor leading to NAFLD. The small intestine is the main site of dietary lipid absorption. A number of clinical trials have shown that acupuncture has positive effects in the regulation of lipid metabolism, which is closely associated with the progression of NAFLD. We therefore hypothesized that, acupuncture can improve the conditions of NAFLD by regulating intestinal absorption of lipid.AIMTo study the role of acupuncture treatment in the improvement of metabolic syndrome secondary to NAFLD by mouse model.METHODS8-wk-old male C57BL/6J mice were fed a methionine- and choline-deficient diet for 3 wk. Then, all mice were separated randomly into acupoints group (AG) or non-acupoints group (NG) with high fat diet feeding. Needling treatment was performed at Zu san li, Guan yuan and Yong quan acupoints as acupuncture treatment to AG mice while non-acupoints place to NG mice. Finally, mice were anesthetized with an injection of ketamine-medetomidine and euthanized by exsanguination.RESULTSAn apparent improvement of obesity was found in AG mice after acupuncture treatment. In AG mice, the body weight was much lower (22.6 ± 1.2 g vs 28.1 ± 1.0 g, P < 0.005) in comparison to NG mice. The length of small intestine in AG mice was significantly shorter (26.7 ± 2.3 cm vs 32.7 ± 2.7 cm, P < 0.005). A large amount of chyme was observed in the lumen of the AG small intestine. The expression of microsomal triglyceride transfer protein, apolipoprotein B and apolipoprotein C2 was downregulated. Triacylglycerols (TGs), total cholesterol and nonesterified fatty acid (NEFA) levels of the small intestinal tissue were significantly higher in AG mice, but the serum TGs and NEFA levels were reduced in AG mice.CONCLUSIONThese results indicate that acupuncture at Zu san li, Guan yuan and Yong quan suppressed lipid absorption by downregulating the expression of apolipoproteins in the small intestine.

Dual real-time in vivo monitoring system of the brain-gut axis

The brain–gut axis which is an interaction between recognition and emotion and the gut sensory system for food and microbiota is important for health. However, there is no real-time monitoring system of the brain and the gut simultaneously so far. We attempted to establish a dual real-time monitoring system for the brain–gut axis by a combination of intravital Ca2+ imaging of the gut and electroencephalogram. Using a conditional Yellow Cameleon 3.60 expression mouse line, we performed intravital imaging of the gut, electrophysiological recordings of the vagus nerve, and electroencephalogram recordings of the various cortical regions simultaneously upon capsaicin stimuli as a positive control. Upon capsaicin administration into the small intestinal lumen, a simultaneous response of Ca2+ signal in the enteric nervous system and cortical local field potentials (LFPs) was successfully observed. Both of them responded immediately upon capsaicin stimuli. Capsaicin triggered a significant increase in the frequency of vagus nerve spikes and a significant decrease in the slow-wave power of cortical LFPs. Furthermore, capsaicin induced delayed and sustained Ca2+ signal in intestinal epithelial cells and then suppressed intestinal motility. The dual real-time monitoring system of the brain and the gut enables to dissect the interaction between the brain and the gut over time with precision.

Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

Патогенетические механизмы лекарственных повреждений печени

Drug-induced liver damage (DILD) is a common condition that can lead in some cases to acute liver failure and unfavorable patient outcomes. DILD development mechanisms are of two main types. The first is a direct dose-dependent type and the second is dose-independent idiosyncratic one. Cytochrome P450 system is of great importance in the genesis of direct DILD, since during drugs metabolism highly toxic metabolites can be formed in this liver enzymatic system. As a result, hepatocytes die destructing mitochondria and thus blocking the production of cell energy substrates, triggering oxidative stress and lipid peroxidation. It also leads to direct DNA damage and activation of signaling pathways for apoptosis. In most cases idiosyncratic DILD is associated with individual genetically determined predisposition with a wide range of clinical manifestations. In case of this type of DILD, the immune cells are sensitized to hepatocytes activating humoral and cellular immune response and rather often forming antibodies to some structural element of hepatocytes. The structure of antigens of the main histocompatibility complex as well as receptor-mediated interactions with Fas-ligand participation, interferon gamma and tumor necrosis factor play a certain role in the development of idiosyncratic DILD. By present, hypotheses of immune system activation in idiosyncratic DILD have been proposed, including haptenization hypothesis; the hypothesis of direct interaction of drugs with the molecules of major histocompatibility complex and subsequent activation of the immune system; the hypothesis of changes in structural sequences of endogenous biologically active peptides with impaired interaction in the backbones of major histocompatibility complex and occurrence of autoimmune reactions. Finally, there is the hypothesis of multiple determinants, which postulates that there are various risk factors (for example, genetic polymorphisms, gender, age, etc.) that contribute to DILD onset in case of comorbidity. DILD mechanisms can also be considered according to clinical and morphological type of liver damage. One can distinguish cholestatic DILD type, vascular type, steatosis, and the type when liver tumor develops. The cholestatic DILD type is clinically expressed by cholestasia or inability of bile to enter the lumen of small intestine as a result of abnormal secretion of bile acids by hepatocytes or obstruction of biliary tract. Hepatic steatosis is histologically determined as deposition of triglycerides within hepatocytes. Drug-induced steatosis is reversible unless steatohepatitis or cirrhosis has developed. Vascular DILD type is associated with damage of stellate and endothelial liver cells, lining sinusoidal capillaries. Edema, thrombosis of small intrahepatic vessels, develop as a result of it, leading to obstruction of venous outflow (and impaired lymph outflow), expansion of sinusoids, pressure overload and hepato-hepatic necrosis, and, in some cases, to centrilobular fibrosis. This pathology is known as sinusoidal obstruction syndrome or venous-occlusive disease. DILD type with the development of liver tumor includes hepatocellular adenoma, hepatocellular carcinoma, cholangiocarcinoma. Awareness of pathogenetic DILD correlations is important in real clinical practice, since, on the one hand, it allows to optimize the diagnostic search for the cause of liver disease, and on the other hand, it increases the effectiveness of approaches to treat and prevent such conditions.

Regulation of Probiotics on Metabolism of Dietary Protein in Intestine.

Proteins are indispensable components of living organisms, which are derived mainly from diet through metabolism. Dietary proteins are degraded by endogenous digestive enzymes to di- or tripeptides and free amino acids (AAs) in the small intestine lumen and then absorbed into blood and lymph through intestinal epithelial cells via diverse transporters. Microorganisms are involved not only in the proteins' catabolism, but also the AAs, especially essential AAs, anabolism. Probiotics regulate these processes by providing exogenous proteases and AAs and peptide transporters, and reducing hazardous substances in the food and feed. But the core mechanism is modulating of the composition of intestinal microorganisms through their colonization and exclusion of pathogens. The other effects of probiotics are associated with normal intestinal morphology, which implies that the enterocytes secrete more enzymes to decompose dietary proteins and absorb more nutrients.

P-glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF-β signaling pathway inhibitor galunisertib.

Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.